JAK-STAT Inhibition in IBD I

Inflammatory bowel disease, or IBD, is characterized by the overexpression of multiple pro-inflammatory cytokines in the gut. Many cytokines that promote inflammation rely on janus kinases, or JAKs, to activate intracellular signaling. There are 4 types of JAKs: JAK1, JAK2, JAK3, and tyrosine kinase-2. JAKs are located on the intracellular portion of the various cytokine receptors on the surface of T cells. JAKs are activated when a cytokine binds to its receptor. Activated JAKs associate with and phosphorylate signaling transducers and activators of transcription, or STATs. The phosphorylated STATs dissociate from the receptor complex and translocate to the nucleus where they regulate gene transcription. Different receptors rely on different combinations of JAKs to exert their effects. JAK inhibitors block cytokine signaling by inhibiting kinase activity. This prevents JAKs from phosphorylating STATs and other substrates, so that intracellular signals cannot be transduced. JAK inhibitors vary in their selectivity for different JAKs. Tofacitinib inhibits multiple JAKs, whereas filgotinib and upadicitinib selectively inhibit JAK1. Based on the role of JAK signaling in inflammation, JAK inhibition is an appealing target for the treatment of IBD.